Safety and tolerability of a multilineage-differentiating stress-enduring cell-based product in neonatal hypoxic-ischaemic encephalopathy with therapeutic hypothermia (SHIELD trial): a clinical trial protocol open-label, non-randomised, dose-escalation trial

Nao Matsuyama, Shinobu Shimizu, Kazuto Ueda, Toshihiko Suzuki, Sakiko Suzuki, Ryosuke Miura, Akemi Katayama, Masahiko Ando, Masaaki Mizuno, Akihiro Hirakawa, Masahiro Hayakawa, Yoshiaki Sato, Nao Matsuyama, Shinobu Shimizu, Kazuto Ueda, Toshihiko Suzuki, Sakiko Suzuki, Ryosuke Miura, Akemi Katayama, Masahiko Ando, Masaaki Mizuno, Akihiro Hirakawa, Masahiro Hayakawa, Yoshiaki Sato

Abstract

Introduction: Neonatal hypoxic-ischaemic encephalopathy (HIE) is an important illness associated with death or cerebral palsy. This study aims to assess the safety and tolerability of the allogenic human multilineage-differentiating stress-enduring cell (Muse cell)-based product (CL2020) cells in newborns with HIE. This is the first clinical trial of CL2020 cells in neonates.

Methods and analysis: This is a single-centre, open-label, dose-escalation study enrolling up to 12 patients. Neonates with HIE who receive a course of therapeutic hypothermia therapy, which cools to a body temperature of 33°C-34°C for 72 hours, will be included in this study. A single intravenous injection of CL2020 cells will be administered between 5 and 14 days of age. Subjects in the low-dose and high-dose cohorts will receive 1.5 and 15 million cells per dose, respectively. The primary outcome is the occurrence of any adverse events within 12 weeks after administration. The main secondary outcome is the Bayley Scales of Infant and Toddler Development Third Edition score and the developmental quotient per the Kyoto Scale of Psychological Development 2001 at 78 weeks.

Ethics and dissemination: This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The Nagoya University Hospital Institutional Review Board (No. 312005) approved this study on 13 November 2019. The results of this study will be published in peer-reviewed journal and reported in international conferences.

Trial registration numbers: NCT04261335, jRCT2043190112.

Keywords: Clinical trials; NEONATOLOGY; Paediatric intensive & critical care.

Conflict of interest statement

Competing interests: SSh, MM, and YS have collaborative projects with research funding from LSII for perinatal diseases. SSh and AH receive fees based on a consultation contract from LSII. SSh, TS, MM, MH, and YS have a patent for the application of Muse cells in the treatment of HIE and other indications. LSII provided CL2020 for this clinical trial free of charge.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
This is a schematic diagram of this clinical trial as a 3 + 3 design. It shows the schedule of enrolment, timing of CL2020 cells administration, assessments and visits for each patient, and timing of the data safety monitoring board (DSMB) meeting. The DSMB meets for the safety evaluation 4 weeks after CL2020 cells administration to the first patient in each cohort and 12 weeks after administration to the third patient in each cohort to confirm if the remaining participants can be enrolled. DSMB, data and safety monitoring board.

References

    1. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010;86:329–38. 10.1016/j.earlhumdev.2010.05.010
    1. Hayakawa M, Ito Y, Saito S, et al. . Incidence and prediction of outcome in hypoxic-ischemic encephalopathy in Japan. Pediatr Int 2014;56:215–21. 10.1111/ped.12233
    1. Lawn JE, Cousens S, Zupan J, et al. . 4 million neonatal deaths: when? where? why? Lancet 2005;365:891–900. 10.1016/S0140-6736(05)71048-5
    1. Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Treat Options Neurol 2012;14:608–19. 10.1007/s11940-012-0200-y
    1. Perlman JM, Wyllie J, Kattwinkel J. Part 11: neonatal resuscitation: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010;122:S516–38. 10.1161/CIRCULATIONAHA.110.971127
    1. Edwards AD, Brocklehurst P, Gunn AJ, et al. . Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340:c363. 10.1136/bmj.c363
    1. Hattori T, Sato Y, Kondo T, et al. . Administration of umbilical cord blood cells transiently decreased hypoxic-ischemic brain injury in neonatal rats. Dev Neurosci 2015;37:95–104. 10.1159/000368396
    1. Tsuji M, Taguchi A, Ohshima M, et al. . Effects of intravenous administration of umbilical cord blood CD34(+) cells in a mouse model of neonatal stroke. Neuroscience 2014;263:148–58. 10.1016/j.neuroscience.2014.01.018
    1. Nakanishi K, Sato Y, Mizutani Y, et al. . Rat umbilical cord blood cells attenuate hypoxic-ischemic brain injury in neonatal rats. Sci Rep 2017;7:44111. 10.1038/srep44111
    1. Cotten CM, Murtha AP, Goldberg RN, et al. . Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr 2014;164:973–9. 10.1016/j.jpeds.2013.11.036
    1. Tsuji M, Sawada M, Watabe S, et al. . Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety. Sci Rep 2020;10:4603. 10.1038/s41598-020-61311-9
    1. Mikrogeorgiou A, Sato Y, Kondo T, et al. . Dedifferentiated fat cells as a novel source for cell therapy to target neonatal hypoxic-ischemic encephalopathy. Dev Neurosci 2017;39:273–86. 10.1159/000455836
    1. Sato Y, Ueda K, Kondo T, et al. . Administration of bone marrow-derived mononuclear cells contributed to the reduction of hypoxic-ischemic brain injury in neonatal rats. Front Neurol 2018;9:987. 10.3389/fneur.2018.00987
    1. Sugiyama Y, Sato Y, Kitase Y, et al. . Intravenous administration of bone marrow-derived mesenchymal stem cell, but not adipose tissue-derived stem cell, ameliorated the neonatal hypoxic-ischemic brain injury by changing cerebral inflammatory state in rat. Front Neurol 2018;9:757. 10.3389/fneur.2018.00757
    1. Kitase Y, Sato Y, Ueda K, et al. . A novel treatment with stem cells from human exfoliated deciduous teeth for hypoxic-ischemic encephalopathy in neonatal rats. Stem Cells Dev 2020;29:63–74. 10.1089/scd.2019.0221
    1. Kuroda Y, Kitada M, Wakao S, et al. . Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci U S A 2010;107:8639–43. 10.1073/pnas.0911647107
    1. Dezawa M. Muse cells provide the pluripotency of mesenchymal stem cells: direct contribution of Muse cells to tissue regeneration. Cell Transplant 2016;25:849–61. 10.3727/096368916X690881
    1. Wakao S, Akashi H, Kushida Y, et al. . Muse cells, newly found non-tumorigenic pluripotent stem cells, reside in human mesenchymal tissues. Pathol Int 2014;64:1–9. 10.1111/pin.12129
    1. Yamada Y, Wakao S, Kushida Y, et al. . S1P-S1PR2 axis mediates homing of Muse cells into damaged heart for long-lasting tissue repair and functional recovery after acute myocardial infarction. Circ Res 2018;122:1069–83. 10.1161/CIRCRESAHA.117.311648
    1. Wakao S, Kuroda Y, Ogura F, et al. . Regenerative effects of mesenchymal stem cells: contribution of Muse cells, a novel pluripotent stem cell type that resides in mesenchymal cells. Cells 2012;1:1045–60. 10.3390/cells1041045
    1. Dezawa M. Clinical trials of muse cells. In: Dezawa M, ed. Muse cells. advances in experimental medicine and biology. vol. 1103. Tokyo: Springer, 2018: 305–7.
    1. Suzuki T, Sato Y, Kushida Y, et al. . Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy. J Cereb Blood Flow Metab 2021;41:1707–20. 10.1177/0271678X20972656
    1. Noda T, Nishigaki K, Minatoguchi S. Safety and efficacy of human Muse cell-based product for acute myocardial infarction in a first-in-human trial. Circ J 2020;84:1189–92. 10.1253/circj.CJ-20-0307
    1. Fujita Y, Nohara T, Takashima S, et al. . Intravenous allogeneic multilineage-differentiating stress-enduring cells in adults with dystrophic epidermolysis bullosa: a phase 1/2 open-label study. J Eur Acad Dermatol Venereol 2021;35:e528–31. 10.1111/jdv.17201
    1. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976;33:696–705. 10.1001/archneur.1976.00500100030012
    1. Abe T, Aburakawa D, Niizuma K, et al. . Intravenously transplanted human multilineage-differentiating stress-enduring cells afford brain repair in a mouse lacunar stroke model. Stroke 2020;51:601–11. 10.1161/STROKEAHA.119.026589
    1. Lester RS. Corticosteroids. Clin Dermatol 1989;7:80–97. 10.1016/0738-081X(89)90010-2
    1. Bayley N. Bayley scales of infant and toddler development. 3rd ed. San Antonio, TX: Psychological Corp, 2006.
    1. Society for the Kyoto Scale of Psychological Development . The Kyoto scale of psychological development 2001: information for standardization and administration. Kyoto, Japan: Kyoto Kokusai Shakai Fukushi Center, 2002.
    1. Fisher RS, Acevedo C, Arzimanoglou A, et al. . ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475–82. 10.1111/epi.12550
    1. Barkovich AJ, Hajnal BL, Vigneron D, et al. . Prediction of neuromotor outcome in perinatal asphyxia: evaluation of Mr scoring systems. AJNR Am J Neuroradiol 1998;19:143–9.
    1. Palisano RJ, Rosenbaum P, Bartlett D, et al. . Content validity of the expanded and revised gross motor function classification system. Dev Med Child Neurol 2008;50:744–50. 10.1111/j.1469-8749.2008.03089.x
    1. Azzopardi DV, Strohm B, Edwards AD, et al. . Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349–58. 10.1056/NEJMoa0900854
    1. Jacobs SE, Morley CJ, Inder TE, et al. . Whole-Body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011;165:692–700. 10.1001/archpediatrics.2011.43
    1. Gluckman PD, Wyatt JS, Azzopardi D, et al. . Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365:663–70. 10.1016/S0140-6736(05)17946-X
    1. Shankaran S, Laptook AR, Ehrenkranz RA, et al. . Whole-Body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574–84. 10.1056/NEJMcps050929
    1. Simbruner G, Mittal RA, Rohlmann F, et al. . Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics 2010;126:e771–8. 10.1542/peds.2009-2441
    1. Zhou W-hao, Cheng G-qiang, Shao X-mei, et al. . Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr 2010;157:367–72. 10.1016/j.jpeds.2010.03.030

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